Vitamin D functions as a powerful immune modulator and its insufficiency has recently emerged as a risk factor for cardiovascular disease (CVD) and insulin resistance in the general population. Recently, the prevalence of vitamin D insufficiency and deficiency was recognized to be very high in the US pediatric population and low serum vitamin D were found to be strongly and independently associated with hypertension, hyperglycemia, and metabolic syndrome, independent of adiposity or other CVD risk factors. As HIV-infected children are expected to live several decades, issues of long- term toxicities, such as CVD and diabetes become increasingly important in the management of HIV. The central hypothesis of our proposed studies is that, vitamin D deficiency is a risk factor for the development of subclinical atherosclerosis and insulin resistance in HIV infected children/young adults, and that the risk is mediated by changes in systemic inflammation. To strengthen the findings from the observational study, we will conduct an interventional study, in which we hypothesize that high doses of vitamin D given to HIV-infected children/young adults with low vitamin D levels will increase 25-hydroxyvitamin D (25(OH)D) levels at a lower extent than in a matched healthy HIV-negative control group, specifically in patients treated with NNRTI, and will reduce inflammation, insulin resistance and dyslipidemias. Detailed measures of vitamin D pathways will also be determined. The use of vitamin D has the potential to have a significant impact on prevention of HIV cardiovascular and metabolic co-morbidities especially given that the intervention can be implemented easily and inexpensively in clinical practice. PUBLIC HEALTH RELEVANCE: Children living with HIV are surviving through adulthood;however they are suffering from several complications of HIV and its therapy, including increased risk of heart disease and diabetes. Vitamin D can positively modify inflammation, a known risk factor for heart disease and diabetes, and as such has been shown in the general population to improve cardiovascular risk. This study will examine the relationship between vitamin D levels and cardiovascular and metabolic complications and the interplay of inflammation. We will also study the effect of vitamin D supplementation in HIV infected children/youths on cardiac and metabolic morbidities. Lastly, a detailed assessment of the effect of HIV therapies on vitamin D metabolism will be undertaken.